This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Cell death is a central phenomenon in the etiology of several human diseases including neurodegenerative disorders. It has been demonstrated that alterations in the cellular redox balance regulate the activation of distinct signaling cascades leading to the progression of a variety of cell death programs. However, the exact mechanisms involved in the regulation of cell death by redox signaling are still far from being understood. The long term goal of our research program is to elucidate the molecular mechanisms by which redox signaling regulates neuronal cell death associated with neurodegenerative diseases. My research group is focused in two areas. First, we are identifying the role of oxidative post-translational modifications by glutathionylation in the regulation of neuronal cell death. Second, we are elucidating the role of the antioxidant enzymes peroxiredoxins in the activation of cell death signaling pathways. Because our primary interest is to determine the role of redox signaling in neuronal cell loss associated with neurodegenerative disorders, we are using both in vitro and in vivo experimental paradigms resembling Alzheimer's and Parkinson's disease to identify the molecular events by which redox signaling regulates neuronal cell death pathways such as apoptosis, necrosis and/or autophagy). For this, we are using a combination of advanced cellular/molecular biology, biochemistry and in vivo experimental approaches such as fluorescent imaging, small interference RNA, mice transgenic/knock-out models and proteomics. To date, we have been successful establishing our experimental models with the aid of three exceptional post-doctoral fellows. We have also recently published one research and one review manuscript which expand on observations regarding the role of redox signaling in the regulation of cell death pathways. We foresee that during the next year we will harvest the fruits of this initial effort, which will be translated in both original research manuscripts and the obtainment of extramural funds.